The activities of meropenem-vaborbactam and comparators against 152 (1.1%) carbapenem-resistant Enterobacterales (CRE) isolates identified among 13,929 Enterobacterales isolates collected from U.S. hospitals during 2016 to 2018 were evaluated. CRE rates were higher in the Middle Atlantic census division (3.5%) than in the other divisions (range, 0.0% for the West North Central division to 1.4% for the West South Central division). Among the CRE isolates, 134 carried carbapenemase genes, and these included 72 isolates carrying bla_KPC-3, 51 isolates carrying bla_KPC-2, 4 isolates carrying bla_NDM-1, 3 isolates carrying bla_SME-4, 2 isolates carrying bla_VIM-1, 1 isolate carrying bla_OXA-232, and 1 isolate carrying bla_KPC-4 Meropenem-vaborbactam was active against 95.4% of the CRE isolates and 94.8% of the carbapenem-producing Enterobacterales (CPE) isolates when applying the CLSI breakpoints. All isolates producing serine carbapenemases were inhibited by meropenem-vaborbactam at ≤8 mg/liter. One Citrobacter freundii isolate carrying bla_KPC-3 had a meropenem-vaborbactam MIC of 8 mg/liter and was resistant according to CLSI breakpoints (the isolate was susceptible when the EUCAST criterion of an MIC of ≤8 mg/liter for susceptible was applied), had disrupted OmpC and OmpF sequences, and overexpressed AcrAB-TolC. All carbapenemase-negative CRE isolates (n = 18) were inhibited by meropenem-vaborbactam at ≤4 mg/liter, and the MIC values of this combination ranged from 0.25 to 4 mg/liter. Among 7 isolates carrying metallo-β-lactamases and/or oxacillinases with carbapenemase activity, meropenem-vaborbactam susceptibility was 14.3% and 57.1% when applying CLSI and EUCAST breakpoints, respectively. CRE isolates were resistant to many comparator agents, and the most active agents were tigecycline, colistin, and amikacin (to which 63.2% to 96.7% of the isolates were susceptible). Understanding the epidemiology of CRE isolates in U.S. hospitals and the resistance mechanisms among these isolates is important to form guidelines for the treatment of infections caused by these organisms, which have high mortality rates.